Management of Refractory Anaphylactic Shock

Definition

Step 1: Recognize and Secure Basics First

Step 2: Escalate Epinephrine - IV Route

IV Epinephrine Infusion (PREFERRED over IV bolus)

• Start at 0.1-0.5 mcg/kg/min IV infusion; titrate to response
• Infusion is more effective than IV bolus and results in lower total dose requirement with a better safety profile
• Use a dedicated line with infusion pump and anti-reflux valve when possible
• Continuous monitoring required: vital signs, 12-lead ECG, mental status

IV Epinephrine Bolus (peri-arrest only)

• 1 mcg/kg IV - reserved for peri-arrest or cardiac arrest scenarios
• Higher risk of dysrhythmias; not routine

Step 3: Aggressive Fluid Resuscitation

• 20-30 mL/kg of crystalloid IV as rapidly as possible, preferably via large-bore cannula
• Balanced crystalloids preferred over 0.9% saline (to avoid hyperchloremic metabolic acidosis and renal vasoconstriction)
• Avoid colloids as first-line (concerns about renal failure and haemostasis disorders)
• Reassess after each bolus; repeat as needed for hemodynamic response
• Avoid high infusion rates for >2 hours (fluid overload risk)

Step 4: Second-Line Vasopressors

No single vasopressor has demonstrated superiority over another. Clinicians should use the agent they are most comfortable with, titrated to clinical response. Echocardiography should be considered to exclude myocardial dysfunction requiring a different treatment strategy.

Step 5: Glucagon - For Beta-Blocker Users

• Glucagon 1-2 mg IV (or 20-30 mcg/kg in children), repeat every 5 minutes until hypotension resolves, then infusion at 5-15 mcg/min
• Glucagon bypasses β-receptor blockade by stimulating adenyl cyclase directly, increasing cAMP and improving cardiac output
• Side effects: nausea, vomiting, hypokalemia, hyperglycemia, dizziness (aspiration risk in semi-conscious patients)

Step 6: Bronchospasm Refractory to Epinephrine

IV aminophylline is NOT recommended. Leukotriene receptor antagonists are ineffective for acute anaphylaxis.

Step 7: Corticosteroids

• Hydrocortisone 200-400 mg IV or methylprednisolone 1-2 mg/kg IV
• Do not rely on these for acute hemodynamic instability - they have delayed onset (hours)
• Primary role: prevent biphasic/protracted reactions (occurring 12-24 hours later), and attenuate late-phase response
• In IgE-mediated reactions: hydrocortisone 0.25-1g IV; in complement-mediated reactions (e.g., protamine): methylprednisolone 1-2g (30-35 mg/kg) IV

Step 8: Rescue / Last-Resort Therapies

Methylene Blue

• 1-2 mg/kg IV over 20 minutes
• Mechanism: inhibits nitric oxide synthase and soluble guanylyl cyclase, thereby reducing pathologic vasodilation (similar to vasoplegia treatment post-cardiopulmonary bypass)
• Currently mentioned in one Spanish guideline; supported by animal models and case reports but not universally recommended
• Consider case-by-case when other second-line vasopressors fail

Extracorporeal Life Support (ECLS/VA-ECMO)

• Indicated for refractory cardiogenic shock from anaphylaxis or cardiac arrest not responding to all pharmacologic measures
• Listed in Miller's Anesthesia (10e) as an indication for VA-ECMO
• Requires specialist centre availability; bridge therapy while mediators clear

Step 9: Airway Re-evaluation Before Extubation

• Persistent facial edema suggests ongoing laryngeal edema
• Keep intubated until edema resolves
• Test for air leak after cuff deflation before extubation
• If airway edema suspected, perform direct laryngoscopy before extubation

Monitoring Requirements

• Continuous vital signs and pulse oximetry
• 12-lead ECG (epinephrine toxicity, arrhythmias)
• Arterial line for beat-to-beat BP in severe cases
• Echocardiography to assess cardiac function/hypovolemia in refractory shock
• Serum tryptase (at 1-2h and 24h) to confirm mast cell activation

Disposition

• All patients with refractory anaphylaxis requiring IV epinephrine or airway intervention: admit to ICU
• Observe minimum 12-24 hours for biphasic reaction risk
• On discharge: prescribe epinephrine autoinjector, antihistamine, and corticosteroids (3-5 days); arrange allergy follow-up

Risk Factors for Refractory Anaphylaxis

• Beta-blocker or ACE inhibitor use
• Concurrent mastocytosis or elevated baseline tryptase
• Hereditary alpha-tryptasemia
• Platelet activating factor-acetylhydrolase (PAF-AH) deficiency
• Intraoperative/perioperative setting (venom, muscle relaxants, latex)

Summary Algorithm

IM Epinephrine x2-3 doses + IV fluids (20-30 mL/kg crystalloid)
         ↓ Still hypotensive/in shock?
IV Epinephrine INFUSION (0.1-0.5 mcg/kg/min, titrate)
         ↓ Still refractory?
Add vasopressor: Norepinephrine OR Vasopressin (0.01 units/min)
         ↓ On beta-blockers?
Glucagon 1-2 mg IV bolus → infusion
         ↓ Refractory bronchospasm?
Neb salbutamol + ipratropium + IV Magnesium sulfate 2g
         ↓ All failing?
Methylene Blue 1-2 mg/kg IV
         ↓ Cardiac arrest / No response?
VA-ECMO (specialist centre)

• Tintinalli's Emergency Medicine, 9th ed., Ch. 14
• Barash Clinical Anesthesia, 9th ed., Ch. on Anaphylaxis
• Miller's Anesthesia, 10th ed., Box 81.2
• Pouessel G et al. "Management of Refractory Anaphylaxis: An Overview of Current Guidelines." Clin Exp Allergy 2024 (PMID 38866583)
• Pouessel G et al. "Refractory Anaphylaxis: A New Entity for Severe Anaphylaxis." J Allergy Clin Immunol Pract 2023 (PMID 37172716)

Glucagon in Refractory Anaphylactic Shock

When to Use Glucagon

• The patient is on beta-blockers (especially non-selective ones, e.g., propranolol, carvedilol) AND
• Shock persists despite adequate doses of epinephrine (IM or IV infusion) + aggressive IV fluid resuscitation

Mechanism of Action

• Binds its own glucagon receptor on cardiomyocytes and smooth muscle
• Directly activates adenylyl cyclase, raising intracellular cyclic AMP (cAMP)
• Produces positive inotropy and chronotropy - completely independent of β-adrenergic receptors
• Also reverses bronchospasm via the same cAMP-mediated pathway

Goldman-Cecil Medicine - Acute treatment of systemic anaphylaxis: glucagon and vasopressin indicated for epinephrine resistance due to β-blocker use

Dosing and Administration

Adults

Pediatric

Preparation

• Glucagon is supplied as a lyophilized powder - must be reconstituted with the provided diluent (or sterile water) before IV use
• Reconstitution: 1 mg glucagon powder + 1 mL diluent = 1 mg/mL solution
• For infusion: dilute in D5W or NS to desired concentration; do NOT use saline containing calcium (may cause precipitation)
• Administer via a dedicated IV line if possible

Practical Administration Steps

1. Confirm beta-blocker use in the patient's medication history (or suspect it if epinephrine response is unexpectedly poor)
2. Ensure epinephrine has been given at appropriate doses first - glucagon is adjunct, not a replacement for epinephrine
3. Reconstitute glucagon and administer the IV bolus over ~5 minutes (rapid IV push can worsen nausea/vomiting and cause hypotension transiently)
4. Position patient supine - glucagon can cause vomiting; protect the airway (aspiration risk in drowsy/obtunded patients)
5. If hypotension improves with the bolus, start the maintenance infusion immediately
6. Continue epinephrine infusion alongside glucagon - they are complementary
7. Monitor blood glucose, electrolytes (hypokalemia), and vital signs continuously

Side Effects to Monitor

Important Caveats

• Evidence base is limited - all evidence is from case reports and expert consensus; no RCTs exist
• Glucagon should only be used after appropriate epinephrine has been tried - some case reports show that inadequate epinephrine dosing preceded glucagon use, and hemodynamic improvement may have occurred with optimal epinephrine alone
• It is a temporizing measure - the definitive treatment remains epinephrine + IV fluids + vasopressors
• Resuscitation Council UK (2021) states: consider glucagon when symptoms remain refractory to epinephrine infusion and adequate fluid resuscitation in beta-blocker users
• Some guidelines also list vasopressin (5-40 IU IV) as an alternative to glucagon for beta-blocker-associated epinephrine resistance

Summary Decision Point

Patient on beta-blockers + shock persists after:
   - Epinephrine (IM x2-3 doses or IV infusion) AND
   - IV crystalloid 20-30 mL/kg
           ↓
GIVE GLUCAGON
   Adult:  1-2 mg IV bolus over 5 min → repeat q5 min → infusion 5-15 mcg/min
   Child:  20-30 mcg/kg IV bolus → infusion 5-15 mcg/min
           ↓
Monitor: glucose, K+, nausea/vomiting, airway
Continue epinephrine infusion alongside

• Tintinalli's Emergency Medicine, 9th ed., Table 14-4, p. 112
• Goldman-Cecil Medicine, International Ed., p. 106
• Resuscitation Council UK, Emergency Treatment of Anaphylaxis, 2021
• Murakami Y et al. "Successful treatment of severe adrenaline-resistant anaphylactic shock with glucagon in a patient taking a beta-blocker." JA Clin Rep 2021 (PMID 34907487)
• Pouessel G et al. "Management of Refractory Anaphylaxis: An Overview of Current Guidelines." Clin Exp Allergy 2024 (PMID 38866583)

Hereditary Hemorrhagic Telangiectasia (HHT) - Osler-Weber-Rendu Syndrome

What Is It?

• Structurally abnormal vascular walls throughout the body
• Formation of telangiectasias (small dilated vessels) and arteriovenous malformations (AVMs) in multiple organs
• Recurrent spontaneous bleeding from affected sites
• Frequency: approximately 1 in 5,000 in the general population

The Classic Clinical Triad (Curacao Criteria)

3 criteria = definite HHT; 2 criteria = possible/suspected; < 2 = unlikely

Temporal Sequence of Manifestations

Childhood      → Epistaxis begins (50% of patients by age 10)
Adolescence    → Skin telangiectasias appear (face, lips, ears, chest, oral mucosa)
4th-5th decade → GI bleeding from telangiectasias and AVMs peaks
                 Visceral AVM complications (pulmonary, hepatic, cerebral, renal)

Organ Involvement - Full Spectrum

Genetics

Pathophysiology in Brief

Key Complications to Watch For

• Iron-deficiency anemia - from chronic GI and nasal bleeding; may be severe
• Stroke / brain abscess - via right-to-left shunting through pulmonary AVMs (paradoxical emboli)
• High-output cardiac failure - from large AV shunts (hepatic or pulmonary)
• Pulmonary hypertension
• Colorectal cancer - specifically in SMAD4 mutation carriers

Diagnosis

• Clinical: Curacao criteria (3 of 4 = definite)
• Genetic testing: 5-gene HHT panel (ENG, ACVRL1, MADH4, RASA1, BMP9) - sensitivity ~87% when all 4 Curacao criteria are present
• Screening for visceral AVMs: Echocardiography with bubble study (pulmonary AVM), CT chest, MRI brain, liver Doppler ultrasound
• Serum tryptase and VEGF levels correlate with severity

Management Highlights

• Epistaxis: Humidification, laser ablation, topical tranexamic acid, bevacizumab, septal dermoplasty
• GI bleeding: Iron supplementation, endoscopic argon plasma coagulation of telangiectasias, tranexamic acid, bevacizumab
• Pulmonary AVMs: Transcatheter embolization (if feeding vessel ≥3 mm)
• Hepatic AVMs: Liver transplantation for end-stage disease
• Cerebral AVMs: Neurosurgical or stereotactic radiosurgery consultation
• Renal AVMs/fistulas: Embolization or surgical management
• All patients: Carry medical alert; avoid anticoagulants where possible; family screening for first-degree relatives

• Sleisenger & Fordtran's Gastrointestinal and Liver Disease, p. 2299-2303
• Quick Compendium of Clinical Pathology, 5th ed., §7.3.4.2
• Grainger & Allison's Diagnostic Radiology, p. 711
• Cummings Otolaryngology, Head and Neck Surgery
• UpToDate: Clinical manifestations of HHT (updated March 2026)